Viable mice harboring the quaking mutation develop a tremor in their limbs. The quaking gene mRNA can be alternatively spliced to produce at least five distinct proteins. Pilotte et al. found that one quaking isoform, QKI-7, caused apoptosis when expressed in fibroblasts or in primary rat oligodendrocytes. QKI-7 expressed in HeLa cells localized to the cytoplasm, whereas other isoforms (QKI-5 and QKI-6) localized to the nucleus. QKI-7-mediated apoptosis was inhibited by coexpression of other QKI isoforms, which heterodimerized with QKI-7 and redirected the localization of QKI-7 to the nucleus. Expression of QKI-7 fused to a nuclear localization signal inhibited apoptosis, suggesting that QKI-7-mediated apoptosis required the cytoplasmic localization of QKI-7. Mapping analyses indicated that expression of the COOH-terminal 14-amino acid fragment of QKI-7 in cells was necessary and sufficient for inducing apoptosis. Coexpressed QKI-5 did not dimerize with the fragment and did not prevent apoptosis, indicating that dimerization leads to sequestration of QKI-7 in the nucleus where its proapoptotic effects can be regulated.
J. Pilotte, D. Larocque, S. Richard, Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer. Genes Dev. 15, 845-858 (2001). [Abstract] [Full Text]